This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakashima, H. Articles by Katano, M. Search for Related Content PubMed PubMed Citation Articles by Nakashima, H. Articles by Katano, M.

Nuclear Factor-B Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

Departments of ¹ Cancer Therapy and Research, ² Anatomic Pathology, and ³ Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Requests for reprints: Mitsuo Katano, Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6941; Fax: 81-92-642-6221; E-mail: mkatano{at}tumor.med.kyushu-u.ac.jp.

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-B (NF-B), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-B p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-B suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-B by inflammatory stimuli, including interleukin-1ß, tumor necrosis factor-, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-B. NF-B-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-B suppressed the enhanced cell proliferation. Our data suggest that NF-B activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-B activation in part through Shh overexpression. (Cancer Res 2006; 66(14): 7041-9)

This article has been cited by other articles:

				R. Soleti, T. Benameur, C. Porro, M. A. Panaro, R. Andriantsitohaina, and M. C. Martinez Microparticles harboring Sonic Hedgehog promote angiogenesis through the upregulation of adhesion proteins and proangiogenic factors Carcinogenesis, April 1, 2009; 30(4): 580 - 588. [Abstract] [Full Text] [PDF]

				M. NAKAMURA, J. WADA, H. SUZUKI, M. TANAKA, M. KATANO, and T. MORISAKI Long-term Outcome of Immunotherapy for Patients with Refractory Pancreatic Cancer Anticancer Res, March 1, 2009; 29(3): 831 - 836. [Abstract] [Full Text] [PDF]

				H. Kasperczyk, B. Baumann, K.-M. Debatin, and S. Fulda Characterization of sonic hedgehog as a novel NF-{kappa}B target gene that promotes NF-{kappa}B-mediated apoptosis resistance and tumor growth in vivo FASEB J, January 1, 2009; 23(1): 21 - 33. [Abstract] [Full Text] [PDF]

				M Mimeault and S K Batra Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer Gut, October 1, 2008; 57(10): 1456 - 1468. [Abstract] [Full Text] [PDF]

				B. A. Yoder and K. H. Albertine Inflammation and Lung Disease in the Neonatal Period NeoReviews, October 1, 2008; 9(10): e447 - e457. [Abstract] [Full Text] [PDF]

				G. Yan, J. Huang, N. R. Jarbadan, Y. Jiang, and H. Cheng Sequestration of NF-{kappa}B Signaling Complexes in Lipid Rafts Contributes to Repression of NF-{kappa}B in T Lymphocytes under Hyperthermia Stress J. Biol. Chem., May 2, 2008; 283(18): 12489 - 12500. [Abstract] [Full Text] [PDF]